Molsoft proposes to develop antagonist lead molecules against the thyroid hormone receptor (TR) with IC50s in the low nanoM range and favorable bioavailability, specificity, and toxicity profiles. Proof of concept was achieved in Phase I Molsoft's virtual ligand screening technology allowed the discovery of 14 small molecule TR antagonists displaying extreme structural diversity, with IC50s ranging from 4 to 30 microM Additionally, the test-case lead optimization scheme designed in Phase I, based on generating focused virtual libraries of molecules easily amenable to organic parallel synthesis, resulted in rapid identification of 2nd generation hits with IC50 in the nanomolar range In Phase II, we propose to conduct full-scale optimization cycles of up to 3 of the hits identified in Phase I We expect that the synergistic efforts of computer modeling specialists at Molsoft, organic parallel synthesis, and TR biology experts at New York University, validated in Phase I, will produce low nanomolar hits in Phase II Additionally, a series of computational tools, in vitro characterization, and preliminary animal studies will be used to evaluate the bioavailability, specificity, and toxicity of active molecules and identify new chemical entities with enhanced likelihood of leading to successful clinical candidates attractive to the pharmaceutical industry.